Trends in add-on medications following metformin monotherapy for type 2 diabetes

BACKGROUND: Although metformin is generally universally recommended as a first-line pharmacologic therapy for most people living with type 2 diabetes, second-line and third-line choices can require a tailored approach to achieve optimal blood glucose and glycated hemoglobin levels. OBJECTIVE: To examine national trends in second- and third-line antihyperglycemic medications following metformin monotherapy, comparing 2015 and 2019. METHODS: This retrospective cohort analysis of deidentified pharmacy claims from a large national pharmacy benefits manager from January 1, 2015, to December 31, 2015, and again in January 1, 2019, to December 31, 2019, included adults (aged ≥ 18 years) continuously enrolled in commercial or Medicare insurance plans who filled an index metformin prescription in either year. Proportions of patients by second-line and third-line antihyperglycemic class were calculated. RESULTS: Second-line use of sulfonylureas (−10.1%; P < 0.001), combination drugs (−3.0%; P < 0.001), and dipeptidyl peptidase-4 inhibitors (−2.0%; P = 0.031) significantly declined, whereas second-line use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) (+4.9%; P < 0.001) and glucagon-like peptide-1 receptor agonists (GLP-1Ras) (+10.0%; P < 0.001) significantly increased. Similarly, third-line use of sulfonylureas declined (−5.5%; P = 0.005), whereas third-line use of SGLT2is (+3.4%; P = 0.005) and GLP-1RAs (+8.3%; P < 0.001) increased. Similar trends between 2015 and 2019 were found in commercial and Medicare subgroups. Among all groups in 2015 compared with 2019, sulfonylureas were the most prescribed second-line class and insulins the most common third-line class. Although SGLT2i and GLP-1RA together represented more than one-third of second-line and third-line prescriptions for commercially insured patients in 2019 (34.3% and 35.0%, respectively), these classes were less frequently prescribed in the Medicare subgroup (18% and 25.6%, respectively). CONCLUSIONS: This report provides updated second-line and third-line antihyperglycemic medication prescribing trends in the United States, which suggests that evidence-based guidelines are being used in practice to prevent complications and individualize diabetes care.


Plain language summary
This study looks at types of medications used to treat adults with diabetes in the United States. After a patient is diagnosed with diabetes, they are usually treated with a medication called metformin. Some patients need medications in addition to metformin to help control blood sugar. This article reports which medications are used for patients who need another medication in addition to metformin. Medications are compared for the year 2015 and again for 2019.

Implications for managed care pharmacy
Our findings suggest that utilization of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are increasing (2015 vs 2019), which has pharmacy budget implications but also aligns with evidence-based practice. However, we also found that the increased use of GLP-1RAs and SGLT2is in 2019 (as compared with 2015) is lower among the Medicare cohort, which might be due to low net-cost options required by insurance plans. The high use of sulfonylureas in older individuals, especially those aged 75 years and older, causes concern because of the higher risk of hypoglycemia associated with these agents.
Diabetes is a chronic metabolic disease frequently associated with substantial adverse health and economic consequences. 1 Without any indication of abatement, diabetes has emerged as one of the most prevalent diseases in the United States, resulting in impaired quality of life, disability, lowered work productivity, and a shortened life expectancy. 1 Of the estimated 34.2 million Americans with diabetes, 90%-95% have type 2 diabetes. 2 The total national diabetes-related health expenditure soared to $294.6 billion in 2019, 3 a near $100 billion increase from that seen a decade prior. 4 Globally, health expenditures attributable to diabetes were estimated to be $966 billion in 2021. 5 Contributing to these expenses, costs of new pharmacologic agents used to manage diabetes have increased markedly over the past 2 decades, making it a top expenditure among therapeutic drug categories. [6][7][8] Reported costs for antihyperglycemic medications rose significantly between 2014 and 2019, with average monthly costs rising 47.5% per patient (from $126.52 in 2014 to $186.58 in 2019). 9 The number of therapeutic classes to treat diabetes has increased substantially over the last several years, with roughly 40 medications in approximately 10 categories now available to treat hyperglycemia. 10 Some of these newer agents (eg, sodium-glucose cotransporter 2 inhibitors [SGLT2is] and glucagon-like peptide-1 receptor agonists [GLP-1RAs]) are being evaluated for additional efficacy outcome benefits for the prevention or treatment of common concomitant conditions seen in patients with diabetes, such as obesity or cardiovascular or renal disease. Metformin is generally universally recommended by clinical practice guidelines as a first-line pharmacologic therapy for most patients, given its low cost, tolerability, and effectiveness. 11 However, first-line therapy will ultimately depend on treatment goals and patient comorbidities, in which some patients with established or increased risk of cardiovascular or renal disease could benefit from alternate agents or combination therapy. Additionally, metformin monotherapy may not be adequate to achieve optimal glycemic control in some patients, particularly over time. In these patients, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (DPP-4is), SGLT2is, GLP-1RAs, basal insulin, or other medications may be added to metformin. The 2022 Standards of Medical Care in Diabetes, released by the American Diabetes Association, recommends SGLT2is and GLP-1RAs among patients with cardiovascular or renal comorbidities. 11 However, these newer medications are more expensive than those in older therapeutic classes. Ultimately, recommendations for second-line and third-line therapy remain nuanced because of the following several key clinical characteristics and patient-centered factors: (1) indicators of high-risk or established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease; (2) hypoglycemia risk; (3) impact on body weight; (4) tolerability/side effects; (5) affordability; (6) patient/ provider preferences; and (7) plan-specified steps required to access higher cost medications. 11 Although prior studies have described trends in pharmacologic therapies for type 2 diabetes, none have included data as recently as 2019, nor have they assessed changes in a national dataset across types of insurance plans (Medicare and commercially insured). 12,13 In this study, we report national trends in second-line and third-line antihyperglycemic medications following metformin monotherapy in the United States between 2015 and 2019, across antihyperglycemic drug classes and insurance lines of business (eg, Medicare vs commercial).

STUDY DESIGN AND SAMPLE
This retrospective cohort analysis examined deidentified pharmacy administrative claims from a large national pharmacy benefits manager from January 1, 2015, to December 31, 2015, compared with January 1, 2019, to December 31, 2019, the first and last year of data available for analysis to examine trends. We included adults aged 18 years or older continuously enrolled in commercial or Medicare insurance plans and who filled a prescription for metformin in the index period (defined as January to March) of either year, with no claim for metformin in the 6 months prior to the index claim. Patients prescribed any nonmetformin antihyperglycemic medication with the index metformin claim or in the 6 months prior were excluded. The second-line or third-line antihyperglycemic medications can either be add-on therapy or a change in therapy (ie, switch) resulting in cessation of prior therapy use. As a result, patients were not required to continue metformin or second-line therapy throughout the analysis periods.

ANALYSIS
For each designated time period, metformin monotherapy users were followed until they filled a nonmetformin antihyperglycemic medication (classified as second-line) or until the end of the year. Patients who filled a second-line medication were further followed until they filled a different antihyperglycemic drug class (classified as third-line) or until the end of the year. Numbers and proportions of patients by second-line and third-line antihyperglycemic drug class were calculated for the overall analytic sample and for commercial and Medicare insurance subgroups. This monotherapy, we found significant differences in secondline use of sulfonylureas, combination drugs, DPP-4is, SGLT2is, and GLP-1RAs between 2015 and 2019. Similarly, significant differences were observed in third-line use of sulfonylureas, SGLT2is, and GLP-1RAs. A previously published study by Ackermann et al analyzed national administrative claims data from 2011 to 2015 and reported higher utilization of sulfonylureas (63% of drug starts) in patients aged 75 years and older. 14 However, as SGLT2is were introduced into the market in 2013, their study observed an uptake of SGLT2i prescriptions. Our study showed a significant difference in second-line use of sulfonylureas (−10.1%; P < 0.001) when comparing 2015 with 2019. Additionally, there was a statistically significant difference in DPP-4i (−2.0%; P = 0.031) prescribing, in addition to SGLT2i (+4.9%; P < 0.001) and GLP-1RA (+10.0%; P < 0.001) use. It is possible that these changes likely reflect implementation of updated clinical prescribing algorithms to use SGLT2is and GLP-1RAs in patients with cardiovascular or renal disease. According to the Centers for Disease Control and Prevention, 39.2% of patients with diabetes also had chronic kidney disease (stages 1-4, based on the updated 2021 chronic kidney disease epidemiology collaboration equation for estimated glomerular filtration rate) from 2017 to 2020. 2 Similarly, patients with diabetes are 2 times more likely to develop cardiovascular disease than people without diabetes. 15 Changes in prescribing practices may also likely reflect less reliance on medications that have not demonstrated such benefits (DPP-4is, sulfonylureas) and are associated with adverse clinical outcomes such as hypoglycemia, especially in the older patients (sulfonylureas). 11 Therefore, our findings of national changes in prescribed diabetes medications are to be expected and in line with other findings in the literature and clinical practice trends. 12,13 SGLT2is and GLP-1RAs provide important clinical advantages to patients in addition to lowering blood glucose and glycated hemoglobin (HbA1c) levels, such as blood pressure reduction and weight loss. There are several key established and emerging indications to consider when prescribing SGLT2is and GLP-1RAs over other therapies. 16,17 Most importantly, results from cardiovascular outcomes studies and clinical trials, required by the US Food and Drug Administration, revealed the ability of SGLT2is to protect against major cardiovascular events in patients with established atherosclerotic cardiovascular disease, lower the risk of inpatient admission for heart failure, and decrease cardiovascular and all-cause mortality. 16, [18][19][20][21] Furthermore, studies have demonstrated clinical benefit of SGLT2is and GLP-1s to patients with chronic kidney disease and cardiorenal disease. 18,[23][24][25][26] In a retrospective cohort study was deemed exempt by the University of Pittsburgh Institutional Review Board.

Results
The overall analytic sample increased from 31,750 (0.22%) patients in 2015 to 43,236 (0.22%) patients in 2019 (Table 1), which is in line with increases in nationwide prevalence for patients with type 2 diabetes who are new to therapy during these time periods (52, 865 [0.36%] in 2015 and 67,213 [0.33%] in 2019). On average across both years, 55% of the study population were women, 51% were aged between 45 and 64 years, 25% were aged 65 years and older, and 24% were aged between 18 and 44 years. More than 80% were enrolled in a commercial plan, whereas the rest were enrolled in Medicare.
Sulfonylureas represented the most commonly prescribed second-line class, despite lower utilization in 2019 than in 2015. Insulins were the most common third-line class among all groups in 2015 and in 2019 (Table 1, Figure 1). Long-acting insulins were the most common insulin type used, followed by rapid-acting insulins (data not shown). In 2019, more than one-third of second-line and third-line prescriptions for commercially insured patients consisted of SGLT2i and GLP-1RA medications (34.3% and 35.0%, respectively). However, in the Medicare subgroup, we observed that SGLT2i and GLP-1RA medications were less frequently prescribed (18% and 25.6%, respectively) as second-line and third-line medications.

Discussion
In this examination of second-line and third-line antihyperglycemic medication trends following metformin Although SGLT2i and GLP-1RA therapies may provide excellent clinical benefits to patients in the treatment of diabetes and other comorbidities, there are additional patient preferences and cost considerations. SGLT2i medications are all available as oral tablets, as opposed to most of the GLP-1RA agents, which are self-deliverable subcutaneous injections except for one oral GLP-1RA agent study by Newman et al, patients who switched to an SGLT2i or GLP-1RA agent from a DPP-4i saw a 39% reduction (incidence rate ratio [IRR] = 0.61; 95% CI = 0.38-0.96) and 29% reduction (IRR = 0.71; 95% CI = 0.52-0.97) in inpatient all-cause hospitalizations, respectively. 27 Such reductions in hospitalizations may offset the high pharmacy prices of these medications.   from a DPP-4i to a GLP-1RA that are not seen when switching to SGLT2i medications. This is likely due to the fact that SGLT2i medications are priced similarly to DPP-4i medications. 11 Those who switched to a GLP-1RA agent experienced significantly higher total pharmacy costs (semaglutide) currently on the market. SGLT2i and GLP-1RA medications are newer branded products, which are more costly than other antihyperglycemic agents, particularly generic sulfonylureas. 11

Conclusions
This report provides an updated view of second-line and third-line antihyperglycemic medication prescribing trends in the United States. Although the proportion of patients initiating sulfonylureas following metformin monotherapy was observed to be lower in 2019 than in 2015, sulfonylureas remain the leading second-line choice, despite a lack of evidence for improving cardiovascular outcomes and potentially increasing hypoglycemia risk. 11,29 We suspect that the popularity of sulfonylureas rests on low relative cost, effective lowering of A1C, 29 and clinical inertia. Although we did not assess the relative uptake of these evidence-based medications for patients with established comorbidities such as cardiovascular disease, renal disease, and obesity (ie, SGLT2i, GLP-1RA), it is likely that such comorbidities are impacting choice of second-line and third-line therapies, consistent with reports of their increased overall benefit. 9

ACKNOWLEDGMENTS
This work was supported as part of an ongoing collaboration between the UPMC Center for High-Value Health Care and Evernorth. We thank Yan Huang and Monal Kohli for project analytic support.
(adjusted difference of $2,453.10; 95% CI = $1,837.20-$3,069.00). 27 Findings from a cost-effectiveness analysis of patients on metformin who received a sequential glucose-lowering therapy showed that SGLT2i users had lower total medical costs compared with other second-line diabetes treatment regimens, including GLP-1RA and DPP-4i users. 28 Overall, SGLT2i and GLP-1RA agents provide patients with demonstrated better clinical outcomes (eg, A1c-lowering ability, cardiovascular/weight/renal), which could result in lower medical expenses for those on these medications. Future studies should assess the impact of antihyperglycemic medication prescribing patterns on the total costs of care.

LIMITATIONS
This study has several limitations to consider that are inherent with analyzing and interpreting claims data.
The study population included a disproportionally high sample of patients enrolled in commercial plans, as compared with those on Medicare, which likely influenced the overall findings, as low net-cost options are required by insurance plans. Commercially insured patients have access to drug coupons to mitigate higher copays, and Medicare patients may be subject to higher copays if they reach the Medicare coverage gap. Additionally, patient preferences will influence which medications are taken (ie, medications taken orally as opposed to those taken by injection may be preferred). Furthermore, because patients had to be continuously eligible to be included in the study, our analysis was restricted to only commercial and Medicare plans. As such, the sample may not be representative of a national enrollee population, thereby limiting the generalizability of study findings. The nonavailability of medical claims data prevented us from examining metformin dosage or